1. Field of the Invention
The present invention is directed to a composition that can be used to create a solid mass in a bodily cavity within a living organism. More particularly, this invention relates to an occlusive composition comprising a monomer having two or more reactive cyanoacrylate sites, wherein the polymeric solid formed therefrom has reduced toxicity.
2. Background
The ability to create a solid mass in a bodily cavity can be beneficial in a variety of situations. For example, a solid occlusion can be used to block fallopian tubes for sterilization, to control bleeding from a wound or during surgery, or to cut off blood flow to a tumor, or to a diseased blood vessel, such as an arteriovenous malformation (AVM), an aneurysm, or an arteriovenous fistula.
There are a number of known methods for creating occlusions, each of which involves introducing a solid obstruction into a luminal cavity. Examples of solid obstructions include thin wire microcoils of platinum or stainless steel, and water-insoluble polymers.
A solid occlusion can be created from a water-insoluble polymer in a number of ways. For example, a preformed polymer can be dissolved in a suitable solvent, such as ethanol, and then injected directly into a luminal cavity. Upon contacting the aqueous fluid in the lumen (usually blood), the polymer precipitates from the solution and blocks the passageway. See, e.g., U.S. Pat. No. 6,160,025 (Slaikeu et al.). Alternatively, a reactive monomer can be introduced into the lumen. When the monomer contacts the aqueous, anion-containing fluid (e.g., blood), it polymerizes in situ, blocking the passageway. See, e.g., U.S. Pat. No. 5,695,480 (Evans et al.).
The reactive monomers most commonly used for in situ polymerization are alkyl-2-cyanoacrylates having one polymerizable cyanoacrylate group per monomer, such as n-butyl-2-cyanoacrylate. Upon contact with anions, these monomers react quickly to form linear polymers. The rapid rate of polymer growth causes a rapid increase in viscosity, which is necessary for localized formation of an occlusive mass.
However, the simple alkyl-2-cyanoacrylates have a number of drawbacks. For example, they generate an undesirable amount of heat as they rapidly polymerize. Also, the rapidly forming, adhesive polymers can trap the injection catheters, making it difficult to safely remove the instruments. Moreover, if an occluded lumen is to be resected, the occlusive polymer formed from a common alkyl-2-cyanoacrylate monomer is often too stiff or too brittle to be easily removed during resection. In addition, such polymers release the toxic chemical formaldehyde as they break down. Another drawback of the simple alkyl-2-cyanoacrylates is that the unreacted monomers themselves can cause toxic effects in surrounding tissues. See, e.g., Vinters et al., “The Histotoxicity of Cyanoacrylate: A Selective Review,” Neuroradiology 27, 279-291 (1985).
A potential means of addressing these drawbacks is to increase the chain length of an alkyl-2-cyanoacrylate, which may decrease the rate of biodegradation, and thereby reduce toxicity. But increasing chain length also may slow the rate of polymerization. And while slowing the polymerization rate has the benefit of reducing both heat generation and the risk of catheter entrapment, it also reduces the rate of viscosity increase—which may undermine the usefulness of long chain alkyl-2-cyanoacrylates as occlusive agents. See, e.g., Oowaki et al., “Non-adhesive cyanoacrylate as an embolic material for endovascular neurosurgery,” Biomaterials 21(10), 1039-46 (2000).
Consequently, the most common way that the prior art has addressed these and other problems associated with alkyl-2-cyanoacrylate monomers has been to combine various additives with the monomers, thereby increasing the complexity of the compositions. For example, U.S. Pat. No. 6,037,366 (Krall et al.) describes the use of a composition comprising six additives in two mixtures, which must be combined within four hours of use. Other prior art solutions are described in U.S. Pat. No. 5,624,669 (Leung et al.), where formaldehyde scavengers are used as additives, and WO 00/44287 (Krall et al.), where polymerization inhibitors are added to the embolic composition. By way of example, the typical formulation of an n-butyl cyanoacrylate embolic composition, such as TRUFILL-nBCA (Cordis Neurovascular, Inc., Miami Fla.), requires the physician to mix the monomer with an ethiodized oil additive as a polymerization inhibitor.
Thus, a need exists for an occlusive composition comprising a reactive monomer having the following properties: a) the reactive monomer polymerizes upon contact with an aqueous ionic environment, b) the viscosity of the polymerizing mass increases rapidly enough to create a highly localized occlusion in a high fluid flow environment, c) the polymerization rate is slow enough to minimize heat generation, d) the growing polymeric mass does not impede the removal of an injection catheter, e) the resulting polymeric mass has minimal toxicity, and f) the resulting mass is flexible enough to facilitate resection. A need especially exists for an occlusive composition having these attributes, wherein the composition does not contain a complex mixture of additives.